Metabolism, insulin and other hormones

Metabolism literally means transformation but has become a general term that encompasses all chemical processes that occur in the living body; processes that are the essence of life. These include processes that build up tissues (anabolism) and that make tissues function, which generally cost energy, and processes that degrade tissues (catabolism), which generally produce energy. However, a full description of everything that goes on in the body is beyond our scope: in this section we will focus on the normal physiology of processes that are related to the handling of nutrients (sugars, proteins and fat) and their regulation, with particular attention for the processes that become disturbed in diabetes.

What is Metabolism?

Metabolism refers to the pathways of biochemical processes (metabolic pathways) that occur in all living organisms to maintain life[4][5][6]. These biochemical processes allow us to grow, reproduce, repair damage, and respond to our environment. Throughout its lifetime the body undergoes cycles of building and degradation, taking up fuel and building blocks in the form of food, ultimately to lose them as water, carbon dioxide, urea nitrogen and 'toxic waste'.

Metabolism can be divided into two opposing catagories: anabolism - the building up of things by a succession of chemical reactions that construct or synthesize molecules from smaller components, requiring energy in the process; and catabolism - the breaking down of things, the series of degradative chemical reactions that break down complex molecules into smaller units, which can be oxidized further releasing energy in the process[4][5][6]. Catabolism generally yields energy at the price of loss of stores. During periods of growth, anabolism clearly needs to exceed catabolism. Although the body can go through longer periods of catabolism (e.g. during illness), for survival the long-term balance between anabolism and catabolism should be neutral or slightly positive so that critical bodily functions and structures can be maintained.

Anabolism. The anabolic process uses monomers to build polymers, large complex molecules composed of many small molecules that are similar to each other. Examples are: (i) the synthesis of glucose from smaller carbohydrates (gluconeogenesis) and their storage as the large branched-chain polymer glycogen (glycogenolysis ); (ii) the synthesis of fatty acids from smaller 2 carbon units of acetyl CoA (fatty acid synthesis) and their storage as lipid energy reserves (lipogenesis); and (iii) the synthesis of proteins from activated amino acids (protein synthesis) by ribosomes that translate the order of nucleotides in the messenger RNA copy of the coding portion of the gene responsible. Classic anabolic hormones include: the peptide hormones - growth hormone, insulin-like growth factors IGF-1 and IGF-2, and insulin, and the steroid hormones - testosterone and estrogen[4].

Catabolism. Catabolic processes in living cells break down polymers into their constituent monomers. These monomers can be further broken down to CO2 and H2O generating energy in the form of ATP in the process. Examples are: (i) the break-down of glycogen into glucose (glycogenolysis) and its further catabolism to pyruvate (glycolysis ), then acetyl CoA which can be subsequently oxidised to CO2 and H20 by the tricarboxylic acid cycle and oxidative phosphorylation or used to synthesis fatty acids; (ii) the breakdown of stored lipids to free fatty acids (lipolysis) and their subsequent breakdown to multiple units of acetyl CoA (fatty acid oxidation) and ketone bodies which can be fully oxidised to generate ATP via the TCA cycle and oxidative phosphorylation; and (iii) the break-down of proteins into their constituent amino acids which if not required for protein synthesis are metabolised further. Most of their amino groups are converted into urea through the urea cycle, whereas their carbon skeletons are transformed into acetyl CoA, acetoacetyl CoA and pyruvate or one of the intermediates of the tricarboxylic acid cycle which can be oxidised further or used for the synthesis of fatty acids, ketone bodies and glucose. Classic catabolic hormones include: cortisol - the ‘stress hormone’, adrenalin the ‘fight or flight’ hormone and glucagon[4].

Metabolic connections

Figure 1. Interplay between different metabolic pathways. Ketone body synthesis occurs in the liver and releases ketone bodies into the circulation for use by peripheral (non-liver) tissues. (Click for enlarged view).There are three groups of molecules that form the core building blocks and fuel substrates in the body: carbohydrates (glucose and other groups of sugars); proteins and their constituent amino acids; and lipids and fatty acids. The interplay between glucose metabolism, protein metabolism, amino acid metabolism, lipid metabolism and ketone body metabolism is summarized in Figure 1. Glucose metabolism involves glycogenesis, glycogenolysis, glycolysis, gluconeogenesis, the tricarboxylic acid cycle (TCA), and oxidative phosphorylation; lipid metabolism involves lipid synthesis (lipogenesis) and oxidation (lipolysis) via the TCA cycle and oxidative phosphorylation; protein and amino acid catabolism feeds into the anabolic pathways of gluconeogenesis and lipogenesis as well as the energy generation pathways of the TCA cycle and oxidative phosphorylation and ketone body metabolism links fatty acid metabolism, carbohydrate metabolism and amino acid metabolism. A general description of these biochemical processes is provided in the link Metabolic pathways.

Blood glucose concentration is a function of the rate of glucose entering the circulation from the liver balanced by the rate of glucose removal from the circulation by liver, muscle and brown and white adipose tissue[1][7]. The glucoregulatory hormones of the body are designed to maintain circulating glucose concentrations in a relatively narrow range. This homeostatic process is controlled mainly by glucagon and insulin, and by autonomic nervous activities that control the metabolic state of liver, muscle and fat tissue and the secretory activity of the endocrine pancreas. Activation or inhibition of the sympathetic or parasympathetic branches of the autonomic nervous systems are controlled by glucose-excited or glucose-inhibited neurons located at different anatomical sites, mainly in the brainstem and the hypothalamus. Activation of these neurons by hyper- or hypoglycemia represents a critical aspect of the control of glucose homeostasis, and loss of glucose sensing by these cells as well as by pancreatic β-cells is a hallmark of type 2 diabetes[7].

In the fasting state

In the fasting state, glucose leaves the circulation at a constant rate. To keep pace with glucose disappearance, endogenous glucose production is necessary. For all practical purposes, the sole source of endogenous glucose production is the liver[1][8]. Renal glucose production contributes substantially to the systemic glucose pool only during periods of extreme starvation. Although most tissues have the ability to hydrolyze glycogen, only the liver and kidney contain glucose-6-phosphatase, the enzyme necessary to convert the resulting glucose-6-phosphate into glucose for release into the circulation[1].

During the first 8–12 hours of fasting, the breakdown of glycogen to glucose (glycogenolysis) is the primary mechanism by which glucose is made available. Glucagon facilitates this process and thus promotes glucose appearance in the circulation. Over longer periods of fasting, glucose, produced primarily from lactate and amino acids (gluconeogenesis), is released from the liver[1]. Maintaining blood glucose levels is critical for brain function, since the brain utilizes glucose as its main energy source[7]. For individuals with diabetes in the fasting state, plasma glucose is derived from glycogenolysis and gluconeogenesis under the direction of glucagon. Exogenous insulin influences the rate of peripheral glucose disappearance and, because of its deficiency in the portal circulation, does not properly regulate the degree to which hepatic gluconeogenesis and glycogenolysis occur[1].

In the fed state

The major determinant of how quickly glucose appears in the circulation during the fed state is the rate of gastric emptying. After reaching a post-meal peak, blood glucose slowly decreases during the next several hours, eventually returning to fasting levels. In the immediate post-feeding state, glucose uptake by skeletal muscle and adipose tissue is driven mainly by insulin (see Insulin-induced glucose transport) as is the stimulation of glucose storage as glycogen (glycogenesis ) and the conversion of glucose to fat by glycolysis and lipogenesis[1][9]. At the same time, endogenous glucose production (gluconeogenesis and glycogenolysis) by the liver is suppressed by (i) the direct action of insulin, delivered via the portal vein, on the liver, and (ii) the paracrine effect or direct communication within the pancreas between the α- and β-cells, which results in glucagon suppression by insulin[1].

Insulin action is carefully regulated in response to circulating glucose concentrations. Insulin is not secreted if the blood glucose concentration is ≤ 3.3 mmol/l, but is secreted in increasing amounts as glucose concentrations increase beyond this threshold. Postprandially, the secretion of insulin occurs in two phases: an initial rapid release of preformed insulin, followed by increased insulin synthesis and release in response to blood glucose. Long-term release of insulin occurs if glucose concentrations remain high[1]. While glucose is the most potent stimulus of insulin, other factors stimulate insulin secretion. These additional stimuli include increased plasma concentrations of some amino acids, especially arginine, leucine, and lysine; incretins (GLP-1 and GIP) released from the gut following a meal; and parasympathetic stimulation via the vagus nerve[1].

Amylin complements the effects of insulin on circulating glucose concentrations by suppressing post-prandial glucagon secretion, thereby decreasing glucagon-stimulated hepatic glucose output following nutrient ingestion[1]. This suppression of post-prandial glucagon secretion is postulated to be centrally mediated via efferent vagal signals. Importantly, amylin does not suppress glucagon secretion during insulin-induced hypoglycemia. Amylin also slows the rate of gastric emptying and, thus, the rate at which nutrients are delivered from the stomach to the small intestine for absorption. In addition to its effects on glucagon secretion and the rate of gastric emptying, amylin dose-dependently reduces food intake and body weight in animal models[1].

Type 1 diabetes has been characterized as an autoimmune-mediated destruction of pancreatic β-cells. The resulting deficiency in insulin also means a deficiency in the other co-secreted and co-located β-cell hormone, amylin. As a result, postprandial glucose concentrations rise due to lack of insulin-stimulated glucose disappearance, poorly regulated hepatic glucose production, and increased or abnormal gastric emptying following a meal[1].

For individuals with diabetes in the fed state, exogenous insulin is ineffective in suppressing glucagon secretion through the physiological paracrine route, resulting in elevated hepatic glucose production. As a result, the appearance of glucose in the circulation exceeds the rate of glucose disappearance. The net effect is postprandial hyperglycemia[1].

Early in the course of type 2 diabetes, postprandial β-cell action becomes abnormal, as evidenced by the loss of immediate insulin response to a meal. Peripheral insulin resistance coupled with progressive β-cell failure and decreased availability of insulin, amylin, and GLP-1 contribute to the clinical picture of hyperglycemia in diabetes[1].

Energy production from glucose

The complete oxidation of glucose to CO2 and H2O involves the conversion of each molecule of glucose to two molecules of pyruvate by glycolysis, the decarboxylation of each pyruvate to acetylCoA by the enzyme pyruvate decarboxylase and the oxidation of each acetylCoA molecule to CO2 and H2O via the tricarboxylic acid cycle (TCA cycle, Krebs cycle) and oxidative phosphorylation. For every molecule of glucose catabolised, a net of 2 molecules of ATP are produced during glycolysis with a further 34 molecules of ATP generated by the TCA cycle and cytochrome system[10].

With the exception of the brain and red blood cells, most other tissues with mitochondria, including resting muscle, rely primarily on fatty acids as an energy source[11]. Exercising muscle uses both fatty acids and glucose for energy, the relative contribution of these energy sources depending on the intensity of the exercise. During both fasting and exercise, fat in adipose tissue is hydrolyzed by hormone-sensitive lipase to give glycerol and free fatty acids[11]. Hormone-sensitive lipase is activated by glucagon (during fasting) or epinephrine (during exercise). The glycerol can be converted to glucose in the liver and is a minor source of glucose. The fatty acids can be catabolized to acetylCoA by the process of β-oxidation and the acetylCoA oxidized to CO2 and water via the tricarboxylic acid cycle (TCA cycle, Krebs Cycle) and the cytochrome system.

During prolonged starvation, the fatty acids can also be converted to ketone bodies in the liver. These ketone bodies can be used as an energy source by all tissues except those lacking mitochondria (eg. red blood cells). Brain adapts slowly to the use of ketone bodies during prolonged starvation[11].

In the fed state

Dietary fat (triglyceride) is hydrolyzed to free fatty acids and glycerol in the intestine by pancreatic lipase. Short chain fatty acids can enter the circulation directly, but most fatty acids are re-esterified with glycerol in the epithelial cells of the intestine. The resulting triglycerides enter the circulation through the lymphatic system as lipoprotein particles called chylomicrons the liver lipoprotein that transports exogenous (dietary) products. The triglycerides in chylomicrons can be cleared by lipoprotein lipase at the endothelial surface of capillaries. The resulting fatty acids can be either: (i) stored as fat in adipose tissue; (ii) used for energy in any tissue with mitochondria and an ample supply of oxygen; or (iii) re-esterified to triglycerides in the liver and exported as lipoproteins called very-low-density lipoprotein (VLDL). VLDL is assembled in the liver from triglycerides, cholesterol and apolipoproteins and transports endogenous products[11]. Once in the blood stream VLDL is converted to low-density lipoprotein (LDL).

In the fed state most tissues rely on glucose as their primary energy source, the exception being exercising muscle[11]. When glucose concentrations are high excess glucose can be converted to glycogen, fatty acids and cholesterol in the liver. This is possible because liver contains both a hexokinase and a glucokinase, both of which catalyse the phosphorylation of glucose to glucose-6-phosphate. Unlike hexokinase, glucokinase is not inhibited by glucose-6-phosphate allowing glucose to be converted into glycogen, fatty acids, and cholesterol in the liver under conditions where blood glucose levels and thus liver glucose-6-phosphate levels are high[9][12].

The major function of glycolysis in the liver is to provide carbons from glucose for de novo lipid synthesis[9]. In liver cells, glycolysis converts excess glucose to pyruvate, which under aerobic conditions is decarboxylated to form acetylCoA. AcetylCoA combines with oxaloacetate to form the tricarboxylic acid, citrate which may be oxidized further via the tricarboxylic acid cycle (Krebs Cycle). Excess citrate that is not oxidized via the tricarboxylic acid cycle is exported to the cytosol, where it is converted back to oxaloacetate and acetyl CoA, the latter providing the building blocks for the synthesis of fatty acids and cholesterol[9].

Energy production from fatty acid oxidation

In tissues that contain mitochondria, fatty acids can be catabolized to acetylCoA by the process of β-oxidation and the acetylCoA oxidized to CO2 and water via the TCA cycle (Krebs Cycle) and the cytochrome system. The amount of energy (ATP) generated per mole of stearic acid (C18) is 120 ATP molecules. In contrast, the complete oxidation of three molecules of glucose (3 x C6 = C18) generates only 90 ATP, 33% less than that generated from stearate[13].

Proteins are naturally occuring macromolecules made up of repeating units of L-amino acids. There are around 20 different amino acids which are categorized as essential amino acids and non-essential amino acids. Essential amino acids are those which cannot be synthesized by the body and thus have to be provided from the diet whereas non-essential amino acids are synthesized by the body. Essential amino acids include valine, leucine, isoleucine, phenylalanine, tryptophan, threonine, methionine, arginine, lysine and histidine; whereas the non-essential amino acids are the remaining from the amino acid pool[14].

The proteins on degradation break down to individual amino acids with each amino acid type having its own metabolic fate and specific function. Not only does this metabolic process generate energy, but it also generates key intermediates for the biosynthesis of certain non-essential amino acids, glucose and fat[14].

Normally the body’s main source of energy is carbohydrates. Amino acids undergo metabolism under three different special situations[14]:

During the regular synthesis and degradation of proteins, certain amino acids resulting from the breakdown of proteins are not required for the synthesis of new proteins and hence are metabolised.

When fasting/starving or in the situation of patients with either (i) uncontrolled diabetes mellitus, (ii) deficiency or unavailability of carbohydrates or (iii) improper utilization of carbohydrates, cellular proteins are broken down to give energy as an alternative for carbohydrates.

If a protein rich diet is ingested and the ingested amino acids exceed the body’s requirement for protein synthesis, the excess amino acids are catabolised as they cannot be stored.

In any of the above situations, amino acids get metabolized in the liver by losing the amino group and forming α-keto acids by either transamination or deamination. These α-keto acids further get metabolised to either three or four carbon units which can either , be converted to glucose as a source of energy (by gluconeogenesis) or be broken down directly via the tricarboxylic acid cycle (Krebs Cycle) to CO2 and H2O and produce energy. Some of the amino group released is used for other biosynthetic pathways whereas the surplus is excreted directly in the urine[14].

Regulation of metabolism

Metabolism is regulated at several levels. At the highest level, signals from the environment such as enteric signals following food ingestion, light signals giving rise to circadian rythmicity, flight/fight/fright signals in relation to external stressors and so on, are integrated in various centers in the brain (mainly in the hypothalamus) and lead to a coordinated and orchestrated reaction of the body through hormonal and neuronal signals to the various tissues and organs.

At the second level of regulation, complex and intertwining pathways of regulating enzymes and molecules may be stimulated or suppressed by the action of hormones on their cellular receptors. Thus, insulin will simultaneously influence many metabolic pathways (with a net anabolic and anti-catabolic effect) although the specific effect may vary depending on the local situation in the tissue or indeed the individual cell.

The third level involves the regulation of the activity of the enzymes involved in metabolic pathways. This may involve the phenomenon of ‘substrate feedback’, where the level of a substrate or an intermediate or end-product activates or inhibits that same metabolic pathway. In addition the enzymes may be activated or inhibited by broader regulatory mechanisms such as phosphorylation by kinases (where ATP is the phosphate donor), or dephosphorylation by phosphatases that have the opposite effect. The overall energy level of the cell is reflected in the ratio of ATP (adenosine triphosphate, the core energy carrying molecule of the cell) over AMP (adenosine monophosphate).